Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various deseases, including acquired immunodeficiency syndrome (AIDS), leprosy, malaria, and graft-versus-host desease (GVHD). It has been also attracting attention because of its efficient antiangiogenetic activity. The effectiveness of the drug in these deseases has been attributed to its specific inhibitory activity on tumor necrosis factor (TNF), -alpha production. Because TNF-alpha, a cytokine medating host defense and immune regulation, with a wide range of activities, has deletorious pathophysiological effects in various deseases, including AIDS,tumors, theumatoid arthritis, and diabetes, its production-regulators are are attracative lead
… Morecompounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer ; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has a afforded a number of pheny1- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure potent inhibitors and pure potent enhancers of TNF-alpha production has been obatined. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists (much more potent than flutamide) and potent aminopeptidase N-inhibitors (more potent than bestatin). Less